Fatigue is a common "ghost" symptom in patients with multiple sclerosis (MS), an autoimmune disease mediated by T cells that target myelin antigens of the central nervous system. As fatigue has been associated with inflammatory states, its occurrence may negatively impact MS progression. The aim of this study was to evaluate the impact of fatigue on the cytokine profile of patients with relapsing-remitting (RR) MS. For our study, blood were collected from MS patients in clinical remission phase with (n=15) and without (n=15) fatigue. Cytokines were detected by ELISA in the plasma and supernatant collected from anti-CD3/anti-CD28-activated T cells or LPS-stimulated monocytes. In some wells, different doses of hydrocortisone (HC) were added at the beginning of the culture. Here, peripheral levels of IL-6 and TNF-α, as well as in vitro production of cytokines related to Th17 (IL-6, IL-17, IL-22, and GM-CSF) or Th1 (IFN-γ) phenotypes, were elevated in fatigued patients and their levels were associated with fatigue severity. The same phenomenon was observed between the production of IL-6, TNF-α, IL-1β, and IL-23 by monocytes and fatigue. Moreover, HC was less efficient in inhibiting in vitro inflammatory cytokine production in patients with fatigue, mainly those produced by both CD8 T cells and monocytes. Our data, although preliminary, suggests that the occurrence of fatigue, by favoring the in vitro production of Th1/Th17-related cytokines and corticoid resistance, may negatively impact the course of MS.